Recently, increased use of insecticide-treated bednets has contributed to a drop in morbidity and mortality in few endemic contries. we are at the tipping point that an efficacious malaria vaccine is urgently needed to accomplish global elimination of malaria, to prevent roll-back malaria fail again. Sterile immunity against malaria can only be developed by immunization with live attenuated parasites. In humans immunized by attenuated sporozoites, parasite development arrests during the asymptomatic liver stage and clinical malaria does not occur. Identification of predictive correlates of protection against sporozoites and liver parasites would greatly accelerate development and testing of an effective recombinant malaria vaccine. A clinical trial is imminent for a genetically-attenuated P. falciparum (PfGAP) vaccine that arrests in the liver. Protective im-munity can also be achieved by exposure to bites from infected mosquitoes combined with anti-blood stage parasite drug chloroquine (CQ) or the anti-liver stage parasite drug primaquine (PQ) treatment. An infection-treatment vaccination (ITV) trial will occur in 2010 to compare the protection induced by ITV-PQ and ITV-CQ. We propose in this project to analyze plasma and PBMC samples from volunteers immunized with gen-etically or chemically attenuated parasite vaccines. We will employ systems approaches (multi-parametric Flow analysis, plasma protein profile, and P. falciparum antigen array analsysis) to delineate the complex regulatory networks upon which protective immune responses are developed by three vaccination strategies, to identify signatures that 1) predict the acquisition of protective immunity after primary immune-ization, 2) discriminate between protective and non-protective immunizations, and 3) predict the duration of protection. We anticipate that the PfGAP, Pf-ITV-PQ, and Pf-ITV-CQ vaccines will induce complete to high levels of pro-tection, but with differences in the pattern of induction, extent of protection, and immune profiles. These dif-ferences will inform our understanding of the correlates of protective immunity against malaria. We will also develop assays for markers that allow prediction of vaccine efficacy to facilitate future trials and identify effective candidates for subunit malaria vaccine development.